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Allergy Apr 2024The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key... (Review)
Review
The importance of allergen immunotherapy (AIT) is multifaceted, encompassing both clinical and quality-of-life improvements and cost-effectiveness in the long term. Key mechanisms of allergen tolerance induced by AIT include changes in memory type allergen-specific T- and B-cell responses towards a regulatory phenotype with decreased Type 2 responses, suppression of allergen-specific IgE and increased IgG and IgG, decreased mast cell and eosinophil numbers in allergic tissues and increased activation thresholds. The potential of novel patient enrolment strategies for AIT is taking into account recent advances in biomarkers discoveries, molecular allergy diagnostics and mobile health applications contributing to a personalized approach enhancement that can increase AIT efficacy and compliance. Artificial intelligence can help manage and interpret complex and heterogeneous data, including big data from omics and non-omics research, potentially predict disease subtypes, identify biomarkers and monitor patient responses to AIT. Novel AIT preparations, such as synthetic compounds, innovative carrier systems and adjuvants, are also of great promise. Advances in clinical trial models, including adaptive, complex and hybrid designs as well as real-world evidence, allow more flexibility and cost reduction. The analyses of AIT cost-effectiveness show a clear long-term advantage compared to pharmacotherapy. Important research questions, such as defining clinical endpoints, biomarkers of patient selection and efficacy, mechanisms and the modulation of the placebo effect and alternatives to conventional field trials, including allergen exposure chamber studies are still to be elucidated. This review demonstrates that AIT is still in its growth phase and shows immense development prospects.
Topics: Humans; Artificial Intelligence; Desensitization, Immunologic; Hypersensitivity; Allergens; Biomarkers; Immunoglobulin G
PubMed: 37984449
DOI: 10.1111/all.15945 -
European Heart Journal. Quality of Care... Aug 2023Randomized controlled trials (RCTs) of lipid-lowering therapy (LLT) in which the control groups received placebo without background LLT offer unique insights into the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Randomized controlled trials (RCTs) of lipid-lowering therapy (LLT) in which the control groups received placebo without background LLT offer unique insights into the placebo and nocebo effects of lipid-lowering RCTs.
METHODS AND RESULTS
Embase and Medline were searched for hyperlipidaemia RCTs with placebo-controlled arms. Placebo arms with background LLT were excluded. A single arm meta-analysis of proportions was used to estimate major adverse cardiovascular events (MACE) and adverse events (AE). A meta-analysis of means was used to estimate the pooled mean differences of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoproteins (HDL) and triglycerides (TG).A total of 40 RCTs and 37 668 placebo-treated participants were included. The pooled mean changes for TC, LDL, HDL, and TG were -0.019 mmol/L, -0.028 mmol/L, 0.013 mmol/L, and 0.062 mmol/L respectively among placebo-treated participants, indicating a modest placebo effect. The pooled average nocebo effect among placebo-treated participants was 42.62% for all AEs and 3.38% for musculoskeletal-related AEs, 11.36% for gastrointestinal-related AEs, and 6.62% for headaches. Placebo-treated participants in secondary prevention RCTs had a far higher incidence of these nocebo effects than primary prevention RCTs: any AEs (OR 6.76, 95% CI: 5.56-8.24, P < 0.001), and gastrointestinal-related AE (OR 1.23, 95% CI: 1.00-1.51, P = 0.049). No differences in nocebo effects were found between the placebo arms of statin and non-statin trials.
CONCLUSION
Our meta-analysis of placebo-treated participants in RCTs with no background LLT indicate a modest placebo effect but prominent nocebo effect of musculoskeletal, headache, and gastrointestinal symptoms that was greatest among secondary prevention RCTs. These findings may inform the design of future LLT RCTs.
Topics: Humans; Nocebo Effect; Randomized Controlled Trials as Topic; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids
PubMed: 36107462
DOI: 10.1093/ehjqcco/qcac060 -
Obesity Reviews : An Official Journal... Feb 2024There is evidence that placebo and nocebo effects are significant for many conditions, but their impact on weight loss has not yet been well described. (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
There is evidence that placebo and nocebo effects are significant for many conditions, but their impact on weight loss has not yet been well described.
MATERIAL AND METHODS
A systematic review of studies indexed on PubMed, Cochrane, PsycINFO, PsycARTICLES, TripDatabase, and Embase was carried out. Studies (1) with at least two study groups - placebo and a corresponding control group; (2) published in English; and (3) focusing on adults participating in weight loss programs or on placebo/nocebo effects in weight loss were included. Synthesis and meta-analysis of the results of studies with comparable research plans were performed.
RESULTS
Some preliminary trends suggesting placebo and nocebo effects in weight loss were found. Placebo effects manifested in trends towards a slightly greater reduction of Body Mass Index (BMI) and body fat ratio in the placebo compared with the control groups. On the other hand, in one study, it was found that the expectancy effects of taking oral weight-loss agents might be disadvantageous (i.e., because they elicit a nocebo effect on weight loss).
CONCLUSION
The findings suggest a possibility that the nocebo effect may occur when an intervention has a medical context. In contrast, the placebo effect can be observed in cases where the intervention is of a different nature. However, considering the low number of studies analyzing the use of placebos in weight loss, new primary research is needed.
Topics: Adult; Humans; Nocebo Effect; Dietary Supplements; Research Design; Diet; Exercise
PubMed: 37950372
DOI: 10.1111/obr.13660 -
Journal of Education and Health... 2024Unpredictable, undesirable, and confusing reactions in the face of psychological or medical interventions make the clinical presentation more complicated and may... (Review)
Review
Unpredictable, undesirable, and confusing reactions in the face of psychological or medical interventions make the clinical presentation more complicated and may represent clinically unexplained symptoms and also disturbed the doctor-patients relationship and decrease patients' benefits of treatment. It seems that negative expectations from the treatment (nocebo phenomenon) can explain such reactions. The aim of the current study is a scoping review and investigate different aspects of the nocebo phenomenon (negative expectations) in clinical interventions. This paper follows a scoping review of the existence, importance, and multidimensions of the nocebo phenomenon in medical and psychological interventions. Data sources include literature databases (ProQuest, PubMed, Google Scholar, and Scopus) reviewed from inception dates to 2023, and the terms negative expectations, nocebo effect, placebo effect, negative placebo, and clinical interventions were searched. The review of the available articles showed that negative expectations play an important role in the process and effectiveness of clinical interventions. Negative expectations (here named nocebo effect) can significantly interfere with rapport and treatment processes. Some underlying components of the nocebo effect include negative expectancies, conditioning, social learning, memory, cognitive distortions, meaning, motivation, somatic focus, negative reinforcements, personality, anxiety, and neurophysiological factors such as CCK, dopamine, and cortisol are proposed for development and presence of nocebo phenomenon in clinical practice. Negative expectations with its biopsychosocial aspects play an important and amazing role in disorganizing medical and psychological interventions. Using appropriate methods to reduce nocebo effects in therapeutic interventions may increase treatment compliance and adherence and increase the effectiveness of interventions.
PubMed: 38726093
DOI: 10.4103/jehp.jehp_269_23 -
Frontiers in Psychiatry 2023Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During...
INTRODUCTION
Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients.
METHODS
Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8.
RESULTS
No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group.
DISCUSSION
Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT01965925.
PubMed: 37732080
DOI: 10.3389/fpsyt.2023.1246149 -
JAMA Surgery Apr 2024
PubMed: 38630450
DOI: 10.1001/jamasurg.2024.0719 -
Scientific Reports Dec 2023Breathwork may offer simple tools for stress resilience. We conducted the largest parallel randomised-controlled trial on breathwork to date (NCT05676658) wherein 400... (Randomized Controlled Trial)
Randomized Controlled Trial
Breathwork may offer simple tools for stress resilience. We conducted the largest parallel randomised-controlled trial on breathwork to date (NCT05676658) wherein 400 participants on the research platform Prolific were randomised, in blocks of 2 via remote software, to coherent breathing at ~ 5.5 breaths/min or a matched attention-placebo at 12 breaths/min, for ~ 10 min/day over 4 weeks. Participants were blinded to their allocated interventions, both of which were paced with equal inhalation:exhalation ratios. There were no differences on credibility and expectancy of benefit between conditions. At the primary timepoint post-intervention for the primary outcome subjective stress, there was no significant group by time interaction (F(1,377) = 0.089, p = 0.765, η < 0.001) nor main effect of group (F = 0.002, p = 0.961, η < 0.001), however there was a significant main effect of time (F = 72.1, p < 0.001, η = 0.161). Similar results were found at 1-month follow-up for stress and for secondary outcomes of anxiety, depression and wellbeing. There were overall improvements on these mental health and wellbeing outcomes from baseline to post-intervention and follow-up across both groups, yet the magnitude of this improvement was not different between arms. Accordingly, we found no measurable effect of coherent breathing over and above a well-designed breathwork placebo at improving mental health and wellbeing. Methodological considerations and recommendations for robust future research are discussed. Funder: Sasakawa Young Leaders Fellowship Fund, Tokyo, Japan.
Topics: Humans; Mental Health; Anxiety; Japan; Tokyo
PubMed: 38092805
DOI: 10.1038/s41598-023-49279-8 -
Comprehensive Psychiatry Nov 2023Placebo and nocebo responses are modulated by the treatment expectations of participants and patients. However, interindividual differences predicting treatment...
BACKGROUND
Placebo and nocebo responses are modulated by the treatment expectations of participants and patients. However, interindividual differences predicting treatment expectations and placebo responses are unclear. In this large-scale pooled analysis, we aim to investigate the influence of psychological traits and prior experiences on treatment expectations.
METHODS
This paper analyses data from six different placebo studies (total n = 748). In all studies, participants' sociodemographic information, treatment expectations and prior treatment experiences and traits relating to stress, somatization, depression and anxiety, the Big Five and behavioral inhibition and approach tendencies were assessed using the same established questionnaires. Correlation coefficients and structural equation models were calculated to investigate the relationship between trait variables and expectations.
RESULTS
We found small positive correlations between side effect expectations and improvement expectations (r = 0.187), perceived stress (r = 0.154), somatization (r = 0.115), agitation (r = 0.108), anhedonia (r = 0.118), and dysthymia (r = 0.118). In the structural equation model previous experiences emerged as the strongest predictors of improvement (β = 0.32, p = .005), worsening (β = -0.24, p = .005) and side effect expectations (β = 0.47, p = .005). Traits related to positive affect (β = - 0.09; p = .007) and negative affect (β = 0.04; p = .014) were associated with side effect expectations.
DISCUSSION
This study is the first large analysis to investigate the relationship between traits, prior experiences and treatment expectations. Exploratory analyses indicate that experiences of symptom improvement are associated with improvement and worsening expectations, while previous negative experiences are only related to side effect expectations. Additionally, a proneness to experience negative affect may be a predictor for side effect expectation and thus mediate the occurrence of nocebo responses.
Topics: Humans; Motivation; Nocebo Effect; Placebo Effect; Anxiety; Surveys and Questionnaires
PubMed: 37862937
DOI: 10.1016/j.comppsych.2023.152431 -
Clinical Pharmacology in Drug... Aug 2023Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the...
Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the potential concentration-QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high-quality, intensive electrocardiogram signal from a single-ascending-dose study in healthy subjects (N = 56) were included in the analysis. The primary analysis was based on a linear mixed-effect model with ΔQTcF as the dependent variable; iberdomide plasma concentration and baseline QTcF as continuous covariates; treatment (active or placebo) and time as a categorical factor; and a random intercept per subject. The predicted change from baseline and placebo corrected (ΔΔQTcF) at the observed geometric mean maximum plasma concentration and 2-sided 90% confidence intervals at different dose levels were calculated. The upper bound of the 90% confidence interval of the model-predicted ΔΔQTcF effect at maximum concentration from the supratherapeutic dose of 6 mg (2.54 milliseconds) is <10-millisecond threshold, suggesting that iberdomide does not have a clinically relevant QT prolongation liability.
Topics: Humans; Moxifloxacin; Fluoroquinolones; Double-Blind Method; Heart Rate; Dose-Response Relationship, Drug
PubMed: 37079714
DOI: 10.1002/cpdd.1254 -
BMJ Evidence-based Medicine Mar 2024The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the... (Meta-Analysis)
Meta-Analysis
The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies.
Topics: Humans; Network Meta-Analysis; Placebo Effect; Meta-Analysis as Topic
PubMed: 37385716
DOI: 10.1136/bmjebm-2022-112197